Pharmaceutical containing N-methylated cyclic undecapeptides

ABSTRACT

Medical preparations (drugs) containing N-methylated cyclic undecapeptides, especially for internal use, characterized by the presence of 0.1 to 20 weight parts of compounds from the group of cyclosporins (A), 0.3 to 60 weight parts of emulsifier (B) containing anhydromanitol oleylether and/or lactoglyceride and/or citrogylceride, 0.1 to 10 weight parts of emulsion stabilizer (C) containing aluminium-magnesium hydroxy-stearate as a lipogel and 0.2 to 40 weight parts of a solvent (D) composed of 1,4: 3,6-dianhydro-2,5-di-O-methyl-D-glucitole and/or 1,3-dimethyl-2-imidazolidone and/or ethanol, with the ratio A:B being equal to 1:05-1:30.

TECHNICAL FIELD

The present invention concerns medical preparations for internal use, orfor another use, containing poly-N-methylated monocyclic undecapeptidescalled cyclosporins.

BACKGROUND ART

This group of stucturally similar peptides called cyclosporins isproduced by some deuteromycetes, such as e.g. Tolypocladium inflatum(Swiss pat. 589 716 and 603 790) or Tolypocladium terricola (Matha etal., Cytobios 69, 163-170, 1992). Besides cyclosporin A (=cyclosporin)of formula I a number of structurally similar natural cyclosporins wasisolated (Traber et al., Helv. Chim. Acta 65, 1655-1667, 1982). Modifiedcyclosporins which were prepared by partial synthesis were describedalso in EPA 0216 122 or in Czechoslovak patent 277 472. ##STR1##

Especially immunosuppressive properties of systemically administeredcyclosporin are used in therapy or during organ transplants or bonemarrow transplants. It is also applicable in treatment of broad range ofautoimmune diseases of inflammatory etiology and also as antiparasitictreatment. Cyclosporin is used e.g. in rheumatic diseases (rheumatoidpolyarthritis), hematologic diseases (aplastic anemia, idiopathicthrombocytopenia), gastric disorders (ulcerating colitis, Crohndisease), dermatic diseases (psoriasis, sclerodermia) and eye diseases(uveitis). Also topical applications have been tested e.g. in treatmentof psoriasis, uveitis and allopecia.

Bioavailability of cyclosporin varies between 20-50% for currentlyavailable dosage formulations (Wood A. J., et al., Transplant Proc., 15,suppl. 2409, 1983). There are significant differences between groups ofpatients. E.g. there is a low bioavailability in liver acceptors, andincreased bioavailability in bone marrow transplantation. Theinterpersonal variability of biovailability is considerably greater,ranging from a few percent to 90%. This is complicated also by thepresence of significant variations in the course of the treatment.

Effective immunosuppressive treatment requires keeping a certain levelof cyclosporin in blood and maintaining this level in certain range. Therange required is always specific depending upon therapeutic goal. E.g.in cases of graft rejection or in treatment of autoimmune disease, it isnecessary to take into account application of another immunosuppressantat the same time. When formulating medical drugs with cyclosporins, itis important to take into account their high lipophilicity. Solubilityof these drugs in water varies usually from 1.6-2.3 mg/100 ml and doesnot exceed 4 mg/100 ml. Cyclosporins are not sufficiently resorbed fromusual carriers in both liquid or solid state. This problem is solved inSwiss patent 636013 by using sezame oil and/or non-ionogenic tensideand/or reesterified non-ionogenic triglyceride and/or a mixturecontaining one or more lecithins, reeesterified non-ionogenictriglycerides or ethyloleate and/or neutral oil.

Another Swiss patent 641356 is trying to improve resorption ofcyclosporins by adding transesterification products of triglycerideswith polyethylenglycols and/or saturated triglyceride of fatty acidand/or mono or diglycerides.

Therapeutically suitable concentrations of cyclosporins in liquidcarriers show low stability towards precipitations from the solutionsand the solutions are usually badly tolerated. Injection preparationscontaining a non-ionogenic tenside (Cremophor EL) can develop theanaphylactic reaction (Lorenc W. et al.: Agents and Actions 12, 64-80,1982) and cause washing out of additives from plastic parts of devicesfor parenteral applications.

An oral formualtion with transesterification product of triglyceridewith polyethylenglycols (Labrafil® M1944 CS) forms an emulsion of v/otype in which phases are easily separated.

Insufficient tolerance of injection cyclosporin preparations containingnon-ionogenic tensides was solved in a French patent 2608427 bypreparing a lyophilisate for ad hoc formulation of sub-micronesuspension. However, this process is energy-consuming when working withlarger volumes of carrier containing ethanol.

Frequent undesirable side effects of cyclosporin treatment includenephrotoxicity, hypertension, hyperkalemia, hyperurikemia,hepatotoxicity, anemia, gastrointestinal intolerance, tremor andparestesia. The most frequent side effect is usually renal dysfunction.Acute cyclosporin nefrotoxicity is dose-dependent. There is acorrelation with the blood level and a decrease in the dose ordiscontinuation of cyclosporin therapy leads to an improvement. However,progressive and irreversible damage of kidneys was reported in patientswith transplants.

A composition of cyclosporin preparation with decreased nephrotoxicitycontaining omega 3 group of unsaturated fatty acids from fish oils wasdescribed in published international patent application WO 87/06463. Adisadvantage of this form is considerable instability of thepolyunsaturated fatty acids towards oxidative effects and unpleasanttaste and odour.

The same is possible to say about similar cyclosporin formulations basedon esential unsaturated fatty acids of evening primrose oil (Oenotherabiennis and Oenothera Lamarckiana), borago oil (Borago officinalis)covered by published international patent application WO 90/03793 orblack currant oil (Ribes nigrum) which is described in publishedeuropean patent application EP 0 321 128.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 depicts a scheme of multi-layered grid structure ofaluminium-magnesium hydroxystearate of empirical formula Al₅ Mg₁₀(OH)₃₁.(C₁₇ H₃₅ COO)₄. FIGS. 2 and 3 shows graphs comparing a dependenceof cyclosporin concentration in blood on time after application of thepreparation according to invention and commercial product to Beagledogs. The determination of the blood levels was made by means of RIAmethods with specific antibodies (FIG. 2) and non-specific antibodies(FIG. 3).

DISCLOSURE OF INVENTION

The principle of new pharmaceutical preparations with N-methylatedcyclic undecapeptides, which are developed especially for internal use,is in the fact that they contain 0.1 to 20 weight parts of compounds /A/from the group of cyclosporins, 0.3 to 60 weight parts of an emulsifier/B/ composed of anhydromannitol oleylether and/or lactoglyceride and/orcitroglyceride, 0.1 to 10 weight parts of emulsion stabilizer /C/composed of aluminium-magnesium hydroxystearate of empirical formula Al₅Mg(OH)₃₁.(C₁₇ H₃₅ COO)₄ in a form of lipogel and 0.2 to 40 weight partsof a solvent /D/ composed of1,4:3,6-dianhydro-2,5-di-O-methyl-D-glucitole and/or1,3-dimethyl-2-imidazolidinone and/or ethanol. The ratio A:B is from1:0,5 to 1:30.

The compounds from the group of cyclosporins are either cyclosporin or/NVa/² cyclosporin. The medical drugs prepared according to the presentinvention may contain also physiologically acceptable carrier based uponsynthetic or plant oil with interfacial tension 10 mN.m⁻¹ to 25 mN.m⁻¹.Lactoglyceride or citroglyceride contain preferably at least 90% ofcompound of general formula ##STR2## where at least one of the R₁, R₂,or R₃ substituents represents a lactic or citric acid moiety, onerepresents a fatty acid moiety C₁₄ to C₁₈ and the remainder is selectedfrom the group consisting of lactic acid moiety, citric acid moiety,fatty acid moiety C₁₄ to C₁₈ and hydrogen. The medical preparations forexternal application contain preferably 1,3-dimethyl-2-imidazolidinoneas a solvent.

The preparations according to the invention are proposed asself-emulgating dispersions of water/oil type stabilized by lipogel ofaluminium-magnesium hydroxystearate. The emulsion part consists of amixture of non-ionogenic tensides with the individual value HLB equal to4-11, which do not contain ethyleneoxide units. With regard tocharacteristic emulgation properties of the tensides used, the externalcontinuous lipophilic phase is selected in such a way as to be formed ofmore polar oils with polarity index 10-25 mN.m⁻¹. Amphiphillic liquidsof higher boiling point are used as solvents of cyclosporins. Theseliquids are miscible with water and most of organic solvents. Theyconsist of 1,4:3,6-dianhydro-2,5-di-O-methyl-D-glucitole and1,3-dimethyl-2-imidazolidinone or physiologically acceptable ethanol.The emulsifier anhydromanitol oleylether/Montanide® 103 is a liquid ofHLB 6.5 which is biodegradable by pancreatic lipases after oralapplication. It is characterized by the following physico-chemicalparameters:

    ______________________________________                                        density/20° C./                                                                             0.97                                                     viscosity/25° C./                                                                           cca 350 mPa · s                                 index of refraction /23° C./                                                                1.474-1.475                                              iodine number        51-60                                                    saponification number                                                                              120-136                                                  hydroxyl number      95-110                                                   acidity number       max. 1.5                                                 peroxide number      max. 2.0 (mmol/kg)                                       ______________________________________                                    

Citroglycerides and lactoglycerides form the second group of emulsifiersused in the preparations made according to the invention. These arecomposed of mixed triacylglycerols where one or two hydroxyl groups areesterified by fatty acids and two or one glycerole hydroxyl isesterified by lactic acid or citric acid. These emulsifiers are made inseveral commercial brands, especially for food industry and they aremarketed under the trade mark AXOL (Th. Goldschmidt AG). LactoglycerideAXOL L61, L62 and citroglyceride AXOL C62 are typical representatives ofthese emulsifiers and they are characterized by the following physicochemical parameters:______________________________________ AXOL L61 AXOLL62 AXOLC62______________________________________melting point 48-53° C.≈45° C. 58-64° C.saponification number 220-260 >295 215-265iodine nummrmax. 3 max. 3 max. 3free fatty acids max. 3% max. 3% max. 3%HLB 5 ± 1 6± 1 10 ± 1______________________________________

Metabolic studies showed that these emulsifiers were totally hydrolyzedin the gastrointestinal tract giving rise to glycerol, fatty acids andcorresponding hydroxycarboxylic acids. Experiments with labelledhydroxycarboxylic acids showed that metabolism of acids bonded by anester group was not significantly different from that of freehydroxycarboxylic acids.

It is generally known that formation of stable emulsion of v/o type ismore demanding as far as mechanical and thermal energy is concerned.Special devices or elevated temperature may be required in emulgatingprocesses in situ in which the dispersion is formed when needed, e.g.before dilution, before application or during contact with body fluids.It is however desirable to achieve homogenous dispersion without specialdevices or elevated temperature. This can be achieved by specialadditives adjusting rheology. These additives can be in a form oflipogel aluminium magnesium hydroxystearate in plant oils. Theselipogels are commercially available as GILUGEL (Giulini Chemie). For thepreparations according to the present invention, the following types aremost suitable: Gilugel MIG containing 80% of neutral oil MIGLYOL 812,Gilugel ALM containing 80% of almond oil and Gilugel CAO containing 80%of castor oil. Gilugel MIG and Gilugel ALM are characterized by thefollowing physico chemical data:______________________________________Gilugel MIG Gilugel ALM______________________________________content ofAl 0.7-1.4% 0.7-1.4%content of Mg 1.7-2.8% 1.7-2,8%content of Al₅ Mg₁₀/OH/₃₁ /C₁₇ H₃₅ COO/₄ 20% 20%content of water 0.4-1.2% 0.1-0.4%density0.985-0.995 0.97______________________________________

The multilayer grid structure of Gilugel is characterised in scheme FIG.1.

Modified--release of cyclosporin is achieved by arrangment of the ratioof emulsifiers and stabilizing agent. It is documented by FIG. 2 andFIG. 3 where time dependencies of blood levels are compared forcommercially available product and for the preparation according to thepresent invention when applied to Beagle dogs.

In relation to emulsifiers used, triacylglycerols are suitable carriers,provided their polarity, expressed as the interfacial tension, is in therange 10-25 mN.m⁻¹. For example the following oil can be used: castoroil/13.7/, milk thistle oil/14.8/, olive oil/16.9/, almond oil/20.3/,and Miglyol 812 /21.3/.

Favourable for use in the preparations according to the invention is themilk thistle oil, prepared from the seed of Silybum marianum by coldpressure or solvent extraction. The fatty acids part of the oilcomprises:______________________________________palmitic acid7.5-12.5%stearic acid 3.5-6.5%oleic acid 20.0-35.0%linoleic acid46.0-65.0%linolenic acid up to 5.0%gadolenic acid up to 1.0%behenic acidup to 2.5%______________________________________

The solvent 1,4:3,6-dianhydro-2,5-di-O-methyl-D -glucitol under the nameArlasolve DMI is produced by the company ICI American Inc. It has thefollowing physico chemicalproperties:______________________________________boiling point approx.234° C.density 25° C. 1,164refractive index 1,467viscosity 25° C.approx. 5 mPa · sdielectric constant approx.7______________________________________

The solvent 1,3-dimethyl-2-imidazolidinone is produced by Mitsui ToatsuChemicals. Both compounds are characterized by high dissolving power forcyclosporins. 1,3-dimethyl-2-imidazolidinone is especially suitable fortopical formulations due to its structural similarity with urea whichimproves skin hydration.

Preparations according to present invention were verified in twopharmacological models in 3 concentrations as described further on.

Influence of topical cyclosporin upon contact dermatitis induced inguinea pigs by 2,4-dinitrofluorobenzene (DNFB).

The topical preparation was tested in three concentrations (2%, 1% and0.1%) against placebo.

Albine twings (females, weight 300-500 g) were used. The animals weresensitized on the base of both ears by 50 μl of 2% or 5% DNFB (AldrichChemie, Germany) dissolved in a mixture of acetone--olive oil (1:1). Theanimals were shaved and depilated after 6 days (Opilca) on both sides.On the following day, 20 μl of 0.5% DNFB dissolved in a mixture aceton:olive oil (4:1) was applied on both sides. Immediately afterwards, 250mg of the cyclosporin was applied on the right side while 250 mg of theplacebo was applied on the lift side. Two controls were used in theexperiment--control 1 (negative with only 20 μl of 0.5% DNFB beingapplied to both sides) and control 2 (positive, non treated with thecompounds tested). The following parameters were assessed: skinthickness (measured one day before, 8, 24, 32, 48 hours afterapplication) and erythrema (evaluated 24 and 32 hours afterapplication). A size of the oedema was determined by subtracting thevalues measured one day before the application. The erythrema wasassessed according to the following scale: 4--protruding and dark redspot, 3--red spot, 2--pink spot, 1--spread small points of pink colour,0--no change. The experiment was repeated twice --the animals weresensitized by 5% or 2% DNFB.

The effect of the compounds tested upon the oedema is depicted in theFIGS. 1a and 1b. Cyclosporin influenced positively development of theoedema in comparison with the placebo with all concentrations used. Theeffect of the compounds upon the erythrema is summarized in thefollowing table. Statistical evaluation was performed by Student t-test.Abbreviation CY A is used for cyclosporin (cyclosporin A).

Sensibilization with 5% DNFB______________________________________ no.of erythrema animals 24 hrs 32hrs______________________________________Control 1 3 0 ± 0 0 ± 0Control2 5 2.40 ± 0.52 2.10 ± 0.88CY A 0.1% 5 0.40 ± 0.55* 0.60 ± 0.55CY A 1% 50 ± 0*** 0.20 ± 0.45**CY A 2% 5 0.20 ± 0.45** 0.20 ± 0.45**placebo 51.27 ± 1.03 1.13 ± 0.64______________________________________

Sensibilization with 2% DNFB______________________________________ no.of erythrema animals 24 hrs 32hrs______________________________________Control 1 3 0.50 ± 0.55 0.50 ±0.55Control 2 5 2.20 ± 0.63 1.50 ± 0.71CY A 0.1% 5 0.20 ± 0.45*** 0.40 ±0.55*CY A 1% 5 0 ± 0*** 0.20 ± 0.45**CY A 2% 5 0 ± 0*** 0 ± 0***placebo5 1.67 ± 0.82 1.27 ± 1.03______________________________________Statistical evaluation was performed by Student ttest and was related toplacebo. *p <0.05 **p <0.01 ***p <0.001

Effect of topical cyclosporin on DTH (a reaction of delayedhypersensitivity) induced by picrylchloride in mice.

The topical preparation was tested in three concentrations 2%, 1% and0.1% in comparison with cyclosporin placebo. A modified method was usedas described by Descotes et al.: Meth. and Find. Exptl. Clin.Pharmacol., 7(6):303-305, 1985. The inbred mice C57BL10/ScSn (females,weight 18-22 g) were used for the experiment. Abdomens of the animalswere shaved on the day 0 and 200 μl of 5% picrylchloride was applied toabdomen and paws. The picrylchloride was dissolved in 100% ethanol.After 7 days, thickness of ears was measured and 50 μl of 1%picrylchloride was applied on both ears. Immediately afterwards, 10 mgof topical cyclosporin was applied to right ear and 10 mg ofcorresponding placebo was applied to left ear. Ear thickness wasmeasured again after 14 hours. The value of oedema was obtained bysubtracting ear thickness after and before the application ofpicrylchloride. Two controls were used for the experiment: control 1(negative, only 50 μl of 1% PiCl was applied on both ears) and control 2(positive, not treated by the compounds tested). Statistical evaluationwas performed by Student t-test and related to placebo. Each groupcontained 10 animals. The following table shows that both cyclosporinand placebo have beneficial effect upon the oedema induced bypicrylchloride. A dose dependence was observed for the effect ofcyclosporin. 2% concentration was the most effective and showedstatistically significantly better than placeboalone.______________________________________ Oedema (mm)%______________________________________Control 1 0.031 ± 0.01542.5Control 2 0.073 ± 0.030 100.0CY A 0.1% 0.016 ± 0.016 21.9CY A 1%0.015 ± 0.012 20.5CY A 2% 0.009 ± 0.009*** 12.3placebo 0.024 ± 0.02032.9______________________________________

Application of high-boiling solvents (Arlasolve DMI, b.p. 234° C. or1,3-dimethyl-2-imidazolidinone, b.p. 225° C.) eliminates familiarproblems with storage of existing oral concentrates and gelatinecapsules based on ethanol which require a special packaging material.The capsules are usually packed in a single bed alu-foil packaging whichmakes the preparation rather voluminous and expansive while liquidconcentrates require special leak-proof bottles with a rubber stop persecured by an aluminium capsule.

The pharmacokinetic study of preparations according to the invention incomparison to the commercial product was carried out after single oraldose 200 mg of cyclosporin using cross-over method in two phases in nineBeagle dogs. Male animals, aged 12 through 36 month, body weight of 9 to13 kg. They were feed with standard pelleted diet in daily dose of 300 gwitch free access to drinking water. Doses were administered in themorning, after 18 hours starvation and swallowing was checked. Next feedwas administered 12 hours later.

Samples of blood were taken in the following intervals:0-0.5-1-2-4-6-8-10-12-24 hours after administration. Samples were frozenand stored at -20° C. until the amalysis by means RIA method with thespecific antibodies, the nonspecific antibodies or HPLC method was done.

In the course of the average concentrations of cyclosporin in blood inthe dependence on time, determinated by specific RIA (FIG. 2) andnon-specific RIA methods (FIG. 3) in the commercial product and thepreparation according to this invention (example 5), there is theevidence to achieve the modified release of cyclosporin in the coarse offirst 10 hours after the administration of the preparation according tothis invention by decreasing of amount of emulsifier with simultaneousincreasing of stabilizing agent in the preparation according to theinvention it is possible to increase bioavailability of cyclosporin fromseparate formulations mentioned in the examples 6 and 2 by theincreasing of the portion ofemulgator.______________________________________ Example No. 6 HPLC HPLCCapsules Capsules fillTime x μg! S.E. x μg!S.E.______________________________________0.5 168.00 40.62 340.20142.271.0 721.40 152.36 819.90 87.282.0 1259.90 199.84 1177.30 85.4464.0951.60 189.51 753.10 78.796.0 628.20 123.70 557.20 97.908.0 541.00115.62 431.10 74.2210.0 521.40 100.27 368.80 70.7512.0 394.80 68.09338.70 79.4924.0 114.50 32.13 169.7043.52____________________________________________________________________________Example No. 2 HPLC Specific.RIA Capsules Capsules fillTime x μg! S.E. xμg! S.E.______________________________________0.5 526.30 158.15 417.83178.601.0 1421.30 277.32 1416.50 253.922.0 1634.20 215.39 1713.33192.494.0 1016.80 124.19 1259.67 154.096.0 761.20 126.27 999.06209.708.0 648.10 137.54 799.00 122.5110.0 593.60 126.39 627.3388.7412.0. 466.80 93.98 562.33 70.4924.0 190.20 49.64 197.8352.26______________________________________

It is possible to reach bioequivalence between separate dosage forms asconfirm pharmacokinetic data of commercial product and preparationaccording to the invention, example No.2.______________________________________ Commercial product Example No.2______________________________________AUC_(0-10h) 11790.5814336.42C_(max) 1985.50 1999.50t_(max) 2 2K_(a) 3.4313.725t_(1/2).sup.(a) 0.202 0.198K_(e) 0.215 0.173t_(1/2).sup.(e) 3.2764.043MRT 6.243 7.389V_(d) 80.380 81.968CL 17.35714.514______________________________________

List of abbreviations used______________________________________AVC areaunder the curve of concentration - time dependence μg · l⁻¹ · h!C_(max)mximum concentration obtained μg · l⁻¹ !T_(max) time to reach theconcentration-time dependence curve peak h!K_(a) first order absorptionrate constant h⁻¹ !t_(1/2).sup.(a) absorption half-life time h!K_(e)first order elimination rate constant h⁻¹ !t_(1/2).sup.(b) eliminationhalf-life time h!MRT mean residend time h!V_(d) volume of distributionl!CL total body clearence l · h⁻¹!______________________________________

MODES FOR CARRYING OUT THE INVENTION

The following examples show some compositions of preparations madeaccording to the invention without having any limiting meaning.

1. Soft gelatine capsule

    ______________________________________                                        Composition: cyclosporin                                                                              1.500       kg                                                     Arlasolve DMI                                                                            2.250       kg                                                     Montanide 103                                                                            2.500       kg                                                     Axol C62   0.500       kg                                                     Gilugel MIG                                                                              1.000       kg                                                     Miglyol 812                                                                              up to 12.000                                                                              litres                                    ______________________________________                                    

Method of preparation:

Axol C62 and Miglyol 812 are mixed at 65° C. and Gilugel MIG isdisperged into a homogenous mixture. A solution of cyclosporin inArlasolve DMI and Montanide 103 is added and stirred until thetemperature drops to ambient. The preparation is filled into gelatinecapsules on a suitable equipment (e.g. Pharmagel Mark III) in such a waythat capsules No. 10 and 20 contain 75 and 150 mg of cyclosporinrespectively.

2. A concentrate for oral application

    ______________________________________                                        Composition: cyclosporin                                                                              1.000       kg                                                     Arlasolve DMI                                                                            1.500       kg                                                     Montanide 103                                                                            3.000       kg                                                     Axol L61   1.000       kg                                                     Gilugel MIG                                                                              1.000       kg                                                     Milk thistle oil                                                                         up to 10.000                                                                              litres                                    ______________________________________                                    

Method of preparation:

Axol L61 is mixed with milk thistle oil at 55° C. and Gilugel MIG isdisperged in the homogenous mixture. The dispersion is mixed with asolution of cyclosporin in Arlasolve DMI and Montanide 103 and themixture is stirred until cooling down to ambient temperature. Thepreparation is filled into glass ampoules under protective atmosphere ofinert gas. The ampoules are marked by volumetric signs.

3. Suppositorium

    ______________________________________                                        Composition: /NVa/.sup.2 cyclosporin                                                                    1.500      kg                                                    Arlasolve DMI                                                                              1.500      kg                                                    Montanide 103                                                                              1.000      kg                                                    Axol L61     1.500      kg                                                    Gilugel CAO  0.500      kg                                                    Witepsol H5  up to 9.000                                                                              litres                                   ______________________________________                                    

Method of preparation:

Axol L61 is mixed with Witepsol H5 at 55° C. and Gilugel CAO isdisperged into the homogenous mixture. A solution of /NVa/² cyclosporinin Arlasolve DMI and Montanide 103 are added and the solution is stirreduntil cooling down to ambient temperature. The preparation is filled ona suitable device into gelatine suppositories of the following sizes:

No. 75 (=675 mg/NVa/² cyclosporin)

No. 15 (=150 mg/NVa/² cyclosporin)

No. 5 (=50 mg/NVa/² cyclosporin)

4. Cream

    ______________________________________                                        Composition:  cyclosporin   2.000 g                                                         1,3-dimethyl-2-                                                                             10.000 g                                                        imidazolidinon                                                                Axol C62      40.000 g                                                        Gilugel ALM   20.000 g                                                        Water         up to 100.000 g                                   ______________________________________                                    

Method of preparation:

Axol C62 is heated to 65° C. and mixed with Gilugel ALM. The mixture isadded to a solution of cyclosporin in 1,3-dimethyl-2-imidazolidinone andstirred in a turbohomogenizer. Water heated to 70° C. is added at thesame time. After the prescribed volume is reached the mixture is stirredby a frame stirrer until cooling down to ambient temperature. Themixture is then filled into containers with mechanical dosage aplicatorSP30.

5. Oral concentrate

    ______________________________________                                        Composition: cyclosporin                                                                              10.000      kg                                                     ethanol    8.000       kg                                                     Montanide 103                                                                            15.000      kg                                                     Gilugel MIG                                                                              15.000      kg                                                     Miglyol 812                                                                              up to 100.000                                                                             litres                                    ______________________________________                                    

Method of preparation:

Cyclosporin is dissolved in ethanol and mixed with Montanide 103.Miglyol 812 is mixed with Gilugel MIG. The cyclosporin solution is addedto oil fraction and the mixture is homogenized. The preparation (100mg/ml) is applied diluted by water or a suitable drink.

6. Oral concentrate

    ______________________________________                                        Composition: cyclosporin                                                                              10.000      kg                                                     Arlasolve DMI                                                                            15.000      kg                                                     Montanide 103                                                                            20.000      kg                                                     Axol C62   10.000      kg                                                     Gilugel MIG                                                                              10.000      kg                                                     Miglyol 812                                                                              up to 100.000                                                                             litres                                    ______________________________________                                    

Method of preparation:

Axol C62 is heated to 65° C. and mixed with Miglyol 812. To thehomogenous mixture is added the solution of cyclosporin in Arlasolve DMIand Montanide 103, than is stirred until cooling down to ambienttemperature. In the mixture is disperged Gilugel MIG by colloid mill.The preparation is filled to gelatine capsules or in the suitablecontainers.

INDUSTRIAL APPLICABILITY

The invention is usable in pharmaceutical industry in manufacturing ofimmunosuppressive preparations and treating of autoimmune diseases.

We claim:
 1. Pharmaceutical preparations with N-methylated cyclicundecapeptides characterized by the following composition: 0.1 to 20weight parts of compounds /A/ from a group of cyclosporines, 0.3 to 60weight parts of emulsifiers /B/ containing anhydromannitol oleyletherand/or lactoglycerides and/or citroglyceride, 0.1 to 10 weight parts ofemulsion stabilizer /C/ having aluminum-magnesium hydroxystearate ofempirical formula Al₅ Mg₁₀ (OH)₃₁.(C₁₇ H₃₅ COO)₄ in a form of lipogel,and 0.2 to 40 weight parts of solvent /D/ containing1,4:3,6-dianhydro-2,5-di-O-methyl -D-glucitole and/or1,3,-dimethyl-2-imidazolidinone, wherein the ratio A:B equals 1:0.5 to1:30.
 2. Pharmaceutical preparations according to claim 1, characterizedby the presence of physiologically acceptable carrier based on syntheticor plant oil with interfacial tension in the range 10 mN.m⁻¹ -25 mN.m⁻¹.3. Pharmaceutical preparations according to claim 1, characterized bythe fact that the compounds from the group of cyclosporins are eithercyclosporin or /NVa/² cyclosporin.
 4. Pharmaceutical preparationsaccording to claim 1, characterized by the fact that the lactoglycerideor citroglyceride contain at least 90% of compound of the generalformula: ##STR3## where at least one of R₁, R₂, and R₃ substituentsrepresents a lactic acid or citric acid moiety, one represents a fattyacid moiety, C₁₄ to C₁₈ and the remainder is selected from the groupconsisting of lactic acid moiety, citric acid moiety, fatty acid moietyC₁₄ to C₁₈ and hydrogen.
 5. Pharmaceutical composition according toclaim 1, wherein the preparation is for internal use.
 6. Pharmaceuticalcomposition according to claim 1, wherein the preparation is forinternal use.